Impact of MRD at HSCT in childhood B-ALL: results from the FORUM trial

During the 50th Annual Meeting of the EBMT, Balduzzi presented data from the prospective FORUM trial on the impact of minimal residual disease (MRD) at hematopoietic stem cell transplantation (HSCT) in children with B-cell acute lymphoblastic leukemia (B-ALL).¹ Below, we summarize the key findings.

Study design¹

• The FORUM trial included patients aged ≥4 years, <18 years at diagnosis, and/or < 21 years at HSCT who were transplanted from a compatible donor.
• Patients were randomized to receive either total body irradiation (TBI) or chemotherapy conditioning (thiotepa/busulfan/fludarabine or treosulfan/fludarabine/thiotepa).
• Graft-versus-host disease (GvHD) prophylaxis with cyclosporine was given to HLA-identical sibling recipients and cyclosporine-methotrexate-antithymocyte globulin was given to HLA-matched recipients.

Key findings¹

• Of the 1,247 eligible patients, 852 had MRD levels prior to HSCT.
• Overall, 79% of patients were MRD-negative (n = 674) and 21% were MRD-positive (n = 178).
• Overall, the 3-year event-free survival (EFS) and overall survival (OS) was significantly higher for MRD-negative vs MRD-positive patients and the 3-year cumulative incidence of relapse (CIR) was higher for MRD-positive patients (Figure 1).
• The 3-year treatment-related mortality rate was similar by MRD status. 

CIR, cumulative incidence of relapse; EFS, event-free survival; MRD, minimal residual disease; OS, overall survival; TRM, treatment-related mortality.
*Data from Balduzzi.^1
†MRD-negative was defined as PCR MRD of 10^-4 or MFC MRD of <0.01%.
^‡MRD-positive was defined as PCR MRD of ≥ 10^-4 or MFC MRD of ≥ 0.01%.

• In the TBI and chemotherapy cohort, the 3-year EFS and 3-year CIR was significantly higher and significantly lower, respectively, for MRD-negative vs MRD-positive patients (Figure 2A and B).
• Among patients with B-ALL (n = 340), the 3-year EFS was higher (79% vs 62%; p = 0.003) and the CIR was lower (14% vs 30%; p = 0.003) for MRD-negative vs MRD-positive patients; this difference was not observed in T-cell ALL. 
• There was a higher incidence of Grade 3−4 acute GvHD among MRD-positive vs MRD-negative patients (37% vs 29%; p = 0.045).
• Multivariate analyses revealed double the risk of relapse and any failure for MRD-positive vs MRD-negative patients.
  • Patients who received chemotherapy conditioning had double the risk of relapse or any failure compared to patients receiving TBI;
  • patients who experienced early relapse had double the risk of failure, either by relapse or death, compared to those experiencing late relapse; and
  • older patients aged >10 years had triple the risk of treatment-related mortality compared to younger patients.

CIR, cumulative incidence of relapse; EFS, event-free survival; MRD, minimal residual disease; TBI, total body irradiation.
*Data from Balduzzi.¹

 

Key learnings
MRD-negative status prior to HSCT was a significant predictor of EFS and OS. MRD-positivity before HSCT was associated with a higher incidence of acute GvHD and CIR. TBI was associated with half the risk of failure and relapse vs myeloablative conditioning.